PROJECT SUMMARY The college years encompass a period of increased risk for substance use, and in particular, cannabis use (CU), as well as a time of increased risk for trauma exposure and resulting posttraumatic stress disorder (PTSD). Given the high comorbidity between substance use disorders such as cannabis use disorder (CUD) and PTSD, as well as the troubling consequences of the comorbidity (e.g., increased risk of suicide and treatment dropout), there is a need to understand the etiologic mechanisms of these commonly comorbid conditions. Two primary phenotypic models exist: self-medication model (i.e., PTSD CUD) and the high-risk model (i.e., CUD PTSD). To date, there are no existing studies longitudinally examining the etiologic models proposed to explain co-occurring CUD and PTSD in a college sample. Thus, Aim 1 will examine these models of comorbidity in a large (N=9,891) longitudinal study of college students (Spit 4 Science [S4S]; NIAAA-R37 AA011408, PIs Kenneth Kendler & Danielle Dick). CU and trauma-related phenotypes have been shown to be moderately heritable. Thus, Aim 2 will use large consortia data to generate aggregate genetic risk of CU via polygenic risk scores (PRS) to examine in relation to CU frequency in S4S. Additional analyses for training purposes include: a) GCTA; b) GWAS to produce summary statistics to contribute to meta-analytic efforts of the consortia; and c) targeted replication of consortia GWAS hits. Given evidence of heritability, as well as overlapping heritability of CU and trauma-related phenotypes, examination of genetic risk is also needed. Thus, Aim 3 will further examine etiologic models proposed to explain CUD and PTSD comorbidity using PRS for CU and PTSD as potential moderators. This NRSA proposal has four training goals, which were developed in collaboration with the mentorship team: 1) to become knowledgeable in the scientific and clinical knowledge of CU and trauma-related phenotypes; 2) to develop expertise in longitudinal modeling and management (i.e., handling of missing data) of phenotypic data; 3) to obtain advanced training in statistical methods for analysis of molecular genetics; and 4) to further advance professional development skills. The training plan to meet these goals includes a number of complementary approaches, such as formal coursework and didactics (e.g., seminars, workshops), individual mentorship, advanced statistical training, dissemination activities, training in the ethical conduct of research, and experience with grantsmanship activities. The proposed NRSA study is also clinically significant, in that it?in combination with studies that come from it?may increase our understanding of genetic and environmental factors underlying CUD and PTSD comorbidity, potentially informing the development of targeted prevention and early intervention strategies. These aims align well with the National Institute on Drug Abuse?s (NIDA) mission, which emphasizes clinically relevant transdisciplinary research. Specifically, these research and training aims align with the NIDA Strategic Plan Goal 1, which is to ?identify the biological, environmental, behavioral, and social causes and consequences of drug use and addiction across the lifespan.?